To make a significant contribution to the field of cancer research today requires a multi-disciplinary approach. Thus, I chose to accept a postdoctoral position wherein I could capitalize on my expertise in organic synthesis and expand my knowledge in the areas of biochemistry, cellular and molecular biology. As a result of my work in the Glazer lab, my desire is to utilize triplex technology as a model in my investigation of altered helical structures and their role in genomic instability. It is my intention to expand my research in the areas of DNA repair and apoptosis. At the completion of the award period, it is my goal to have transitioned into a tenured-track position as an independent scientist with an established cancer research program. Ultimately, my long-term research goal is to unveil new strategies for cancer treatment. DNA is continually exposed to agents that cause damage to its structure, resulting in the loss of vital genetic information. To counteract the potentially devastating effects of such damage, all organisms have evolved a variety of different repair processes. The importance of DNA repair is shown by the existence of several cancer-prone human genetic disorders which are a result of defects in one of these pathways. Naturally occurring DNA sequences capable of forming non-B conformations are abundant in the human genome, and represent a source of genetic instability. In fact, these sequences are believed to be involved in the regulation of several disease-linked genes, including the human c-myc gene. Sequence-specific DNA binding molecules, which result in the formation of unusual structures upon binding to duplex DNA, will be used as a tool to study the role of these structures in genomic instability. Their repair will be examined, along with their ability to activate pro-apoptotic pathways. The long-term goal of this proposal is to understand the molecular mechanisms of DNA damage recognition, and the role of unusual or modified DNA structures in genomic instability. Relevance: Studies have shown that naturally occurring unusual DNA structures play a role in gene expression and genomic instability. An increased knowledge of how cells metabolize these structures will provide insight into the pathogenesis of a number of human diseases including cancer.